chr3-189868597-G-A

Variant names:

• chr3-189868597-G-A
• rs113993967
• NM_003722.5:c.1010G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003722.5(TP63):​c.1010G>A​(p.Arg337Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.89
• Publications: 23 publications found

Genes affected

TP63 (HGNC:15979): (tumor protein p63) This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016]

TP63 Gene-Disease associations (from GenCC):

• ADULT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• limb-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Rapp-Hodgkin syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• premature ovarian failure 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• split hand-foot malformation 4

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• EEC syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_003722.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-189868596-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6548.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the TP63 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 73 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.2077 (below the threshold of 3.09). Trascript score misZ: 3.5096 (above the threshold of 3.09). GenCC associations: The gene is linked to Rapp-Hodgkin syndrome, ADULT syndrome, premature ovarian failure 21, limb-mammary syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, EEC syndrome, split hand-foot malformation, split hand-foot malformation 4.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-189868597-G-A is Pathogenic according to our data. Variant chr3-189868597-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.1010G>A	p.Arg337Gln	missense_variant	Exon 8 of 14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.728G>A	p.Arg243Gln	missense_variant	Exon 6 of 12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.1010G>A	p.Arg337Gln	missense_variant	Exon 8 of 14	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.728G>A	p.Arg243Gln	missense_variant	Exon 6 of 12	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TP63-Related Spectrum Disorders Pathogenic:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 337 of the TP63 protein (p.Arg337Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TP63-related disorders and ectodermal dysplasia and ARVC (PMID: 8456838, 11929852, 16724007, 18603493, 19781362, 27469932). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg298Gln. ClinVar contains an entry for this variant (Variation ID: 6540). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt TP63 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TP63 function (PMID: 11929852, 16724007, 18626511, 20543567). This variant disrupts the p.Arg337 amino acid residue in TP63. Other variant(s) that disrupt this residue have been observed in individuals with TP63-related conditions (PMID: 16724007), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

ADULT syndrome Pathogenic:1

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 23, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;.;.;.;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.041	D;T;T;T;D;D;T;T;T;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;.;D;.
Vest4		0.99
MutPred		0.97		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;.;.;.;
MVP		0.99
MPC		0.78
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113993967; hg19: chr3-189586386; COSMIC: COSV53196709; COSMIC: COSV53196709;